Clinical and Genetic Characteristics of Alagille Syndrome in Adults

Abstract

Background and Aims: Alagille syndrome (AGS) is an autosomal dominant multisystem disorder caused by mutations in the JAG1 and NOTCH2 genes. AGS has been rarely reported in adult patients, mainly because its characteristics in adults are subtle. The study aimed to improve the understanding of adult AGS by a descriptive case series. Methods: Eight adults diagnosed with AGS at our hospital between June 2016 and June 2019 were included in the study. Clinical data, biochemical results, imaging results, liver histopathology, and genetic testing were analyzed. Results: Three female and five male patients with a median age of 24.5 years at the time of diagnosis were included in the analysis. The clinical manifestations were adult-onset (62.5%, 5/8), cholestasis (50%, 4/8), butterfly vertebrae (62.5%, 5/8), systolic murmurs (12.5%, 1/8), typical facies (12.5%, 1/8), posterior embryotoxon, and renal abnormalities (0/8). Genetic sequencing showed that all patients had mutations, with four occurring in the JAG1 gene and four in the NOTCH2 gene. Six were substitution mutations, one was a deletion mutation, and one was a splicing mutation. Five had been previously reported; but the others, one JAG1 mutation and two NOTCH2 mutations were unique and are reported here for the first time. Conclusions: The clinical manifestations highlighted by the current diagnostic criteria for most adults with AGS are atypical. Those who do not meet the criteria but are highly suspicious of having AGS need further evaluation, especially genetic testing.

Exosomal miR‐122, miR‐128, miR‐200, miR‐298, and miR‐342 as novel diagnostic biomarkers in NAFL/NASH: Impact of LPS/TLR‐4/FoxO3 pathway

“…For miR‐298, the current results disclosed a significantly diminished expression level in NAFL and NASH groups when compared with the normal control. This may be due to the contribution of miR‐298 in cell proliferation and apoptosis prevention leading to protection against disease progression, and its role in regulating oxidative stress‐related genes, such as thioredoxin reductase 3 mRNA, which was reported by Li et al [ 52 ] ROC curve analysis revealed that miR‐298 has a strong diagnostic power in discriminating NAFL patients from the normal control group and a highly strong diagnostic power in distinguishing NASH patients from the normal control group. Studies on T2DM published by Sidorkiewicz et al [ 53 ] showed that the ROC curve of miR‐298 yielded an AUC of 0.957, 100% specificity, 91.3% sensitivity, and cut‐off = 1.5.…”

Management of adults with Alagille syndrome

“…There are limited data describing individuals diagnosed with ALGS as adults. The largest series of 8 patients (4 with JAG1 and 4 with NOTCH2 variants) were recently published from China [ 8 ], in which the median age at diagnosis was 24.5 years (range 16–56), and all patients had abnormal liver biochemistry and jaundice at presentation. Although the diagnosis was made in adulthood in this small series, three patients had a history of cholestasis of unknown etiology since childhood.…”

“…Although bile duct paucity has been identified in almost all adult patients with ALGS and hepatic involvement reported in the literature [ 8 – 10 , 54 , 104 , 105 ], it can also be found in patients with primary sclerosing cholangitis, primary biliary cholangitis, cystic fibrosis liver disease, alpha-1 antitrypsin deficiency, and drug induced liver injury [ 106 , 107 ]. Caution must, therefore, be exercised when relying solely on liver histopathology to diagnose ALGS and further supports the importance of utilizing genetic testing (when feasible).…”